Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents

ABSTRACT

A method for the treatment of glaucoma or lowering intraocular pressure in a mammal, involving topically administering to the eye of such mammal a selectively metabolized beta-blocking compound of the formula ##STR1## wherein R may be lower alkyl, lower hydroxyalkyl, lower alkynyl, aralkyl, or an ester-containing group and Ar may be substituted or unsubstituted aromatic; or a pharmaceutically acceptable salt thereof. Because of a relatively long duration of action of such compounds in ocular fluids and a relatively short duration of action in the systemic circulation, such compounds are useful for the treatment of excessive intraocular pressure without substantial systemic effects.

This is a division of application Ser. No. 276,657 filed June 23, 1981,now U.S. Pat. No. 4,402,974.

BACKGROUND OF THE INVENTION

The present invention relates to a method for the treatment of glaucoma.More particularly, the invention relates to a novel method of treatmentof glaucoma or lowering of intraocular pressure by topicallyadministering beta-adrenergic blocking agents to the eye.

Glaucoma is a condition of the eye characterized by increasedintraocular pressure. Untreated, the condition can eventually lead toirreversible retinal damage and blindness. Conventional therapy forglaucoma has involved topical administration of pilocarpine and/orepinephrine, administered to the eye several times daily.

Various beta-blocking agents may also be used to lower intraocularpressure. Such use is described, for example, in reviews by W. P. Bogerin Drugs, 18, 25-32 (1979) and by T. J. Zimmerman and W. P. Boger inSurvey Ophthalmol. 23(b), 347 (1979). The use of beta-blockers for thetreatment of glaucoma is also described in the patent literature. Forexample, U.S. Pat. No. 4,195,085 to Stone discloses a method fortreatment of glaucoma by the ocular administration of a beta-blockingcompound, timolol maleate. U.S. Pat. No. 4,127,674 discloses treatingglaucoma with labetalol, a known antagonist of both alpha and betaadrenergic receptors. However, these methods also possess significantdrawbacks, in that the absorption of the beta-blocking compound into thesystemic circulation can cause undesirable side effects. Such sideeffects result from prolonged beta-blocking action on the heart,bronchioles and blood vessels. For example, according to Physicians'Desk Reference, Charles E. Baker, Jr., 35th Edition, 1981, p. 1233,adverse reactions to the topical use of timolol maleate can includebronchospasm, heart failure, as well as cardiac condition defects.Accordingly, there is a need for a method of treatment of glaucoma orfor lowering intraocular pressure which is relatively free of unwantedsystemic side-effects.

Certain beta-blocking agents which contain enzymatically labile estergroups are known to exhibit short-acting beta-blocking effects in thesystemic circulation. Such short-acting beta-blocking compounds (SAABs)have been suggested for treatment or prophylaxis of cardiac disorders asa means for reducing heart work or improving rhythmicity for a shortduration. Such short-acting beta-blocking compounds avoid the sometimescounterproductive effects of conventional beta-blocking agents, whoseeffects are long-lived and therefore difficult to precisely control.

SUMMARY OF THE INVENTION

In accordance with the present invention, disclosed herein is a methodfor the treatment of glaucoma or for lowering intraocular pressure in amammal, comprising topically administering to the eye of such mammal abeta-blocking compound of the formula: ##STR2## wherein R representslower alkyl of straight or branched carbon chains from 1 to about 10carbon atoms; cycloalkyl of from 3 to about 7 carbon atoms; alkenyl offrom about 2 to about 10 carbon atoms; alkynyl of from 3 to about 10carbon atoms; hydroxyalkyl of from 2 to about 7 carbon atoms; aralkyl,wherein the alkyl portion contains from 1 to about 5 carbon atoms, andthe aryl portion represents substituted or unsubstituted monocyclic orpolycyclic aromatic or heterocyclic ring systems of from about 6 toabout 10 carbon atoms; a group of the formula ##STR3## wherein Zrepresents lower alkylene of straight or branched carbon chains of from1 to about 10 carbon atoms, and R₁ is lower alkyl of from 1 to about 5carbon atoms; and Ar represents substituted or unsubstituted aromatic;or a pharmaceutically-acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The above-mentioned short-acting beta-blocking compounds effectivelyreduce intraocular pressure in the eyes of mammals when topicallyadministered. Because of their short-lived duration of action in thesystemic circulation, toxic side-effects produced by their migration outof the eye are consequently reduced. It has further been discovered thatcertain of these compounds show an increased longevity of effect whenpresent in the ocular fluid compared to the duration of their systemiceffects. Consequently, the present invention resides in the treatment ofglaucoma or lowering intraocular pressure with a beta-blocking compoundwhich exhibits relatively long duration of action while in the ocularfluid, but which is subject to relatively rapid breakdown into inactivemetabolites upon passage to the systemic circulation.

Compounds administered by the method of the present invention arerepresented by the formula: ##STR4## wherein R represents lower alkyl ofstraight or branched carbon chains from 1 to about 10 carbon atoms;cycloalkyl of from 3 to about 7 carbon atoms; alkenyl of from 2 to about10 carbon atoms; alkynyl of from 2 to about 10 carbon atoms;hydroxyalkyl of from 2 to about 7 carbon atoms; aralkyl, wherein thealkyl portion contains from about 1 to about 5 carbon atoms and the arylportion represents substituted or unsubstituted monocyclic or polycyclicaromatic or heterocyclic ring systems of from 6 to about 10 carbonatoms, such as benzyl, phenethyl, 3,4-dimethoxyphenethyl,1,1-dimethyl-2-(3-indolyl)ethyl, and the like; and Ar representssubstituted or unsubstituted aromatic, including monocyclic, polycyclicand heterocyclic ring systems. Aromatic (Ar) substituents may includelower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen,acetamido, amino, nitro, lower alkylamino, hydroxy, hydroxyalkyl, cyano,methylenedioxy, acyloxy, wherein the acyl portion is a straight orbranched chain alkanoyl of from 1 to about 7 carbon atoms or aroyl offrom 6 to about 10 carbon atoms, optionally substituted by halogen,lower alkoxy, lower alkyl, acetamido, cyano or hydroxy, and groups ofthe formula ##STR5## wherein R₁ is lower alkyl, aryl or aralkyl and n isan integer from 0 to about 10. The compounds described herein are notlimited to any particular stereoisomeric configuration. Such compoundsmay be administered as their pharmaceutically acceptable acid additionsalts, e.g., as the hydrochloride, sulfate, phosphate, oxalate,gluconate, tartrate, et cetera.

In preferred compounds R is lower alkyl of from 1 to about 5 carbonatoms, such as isopropyl, n-butyl, t-butyl, n-pentyl, and the like;alkynyl of from 3 to about 5 carbon atoms, such as propargyl,dimethylpropargyl and the like; hydroxyalkyl of from 2 to about 5 carbonatoms, such as hydroxy-t-butyl and the like; or aralkyl wherein thealkyl portion contains from 1 to about 3 carbon atoms and the arylportion contains from 6 to about 10 carbon atoms, such as benzyl,phenethyl, 3,4-dimethoxyphenethyl and the like; and Ar is unsubstitutedphenyl, or phenyl substituted with lower alkyl of from 1 to about 5carbon atoms, fluoro, chloro, nitro, hydroxy, amino, acyloxy, whereinthe acyl portion is alkanoyl of from 2 to about 5 carbon atoms, orbenzoyl optionally substituted by halogen, alkoxy, alkyl or hydroxy, ora group of the formula ##STR6## wherein R₁ is lower alkyl of from 1 toabout 5 carbon atoms, and n is an integer from 0 to about 5. Inparticularly preferred compounds of the present invention, R is lowerhydroxy alkyl or lower alkynyl, most preferably hydroxy-t-butyl ordimethylpropargyl, however, it is to be understood that when Ar isphenyl substituted with two or three hydroxy groups, or phenylsubstituted with acyloxy wherein the acyl portion is alkanoyl from 2 toabout 5 carbon atoms or benzoyl (optionally substituted by halogen,alkoxy, alkyl or hydroxy), R may optionally additionally be isopropyl,t-butyl or dimethoxyphenethyl. Ar is most preferably phenyl or phenylsubstituted with methyl, fluoro, chloro, nitro, hydroxy, amino, acyloxy,such as acetoxy, isobutyryloxy, pivaloyloxy, benzoyloxy or4-methoxybenzoyloxy.

The compounds described herein may be prepared by a number of syntheticmethods, depending upon the particular structure desired.

Compounds of the invention may be advantageously prepared by either ofthe following two methods: ##STR7##

The latter method is particularly preferred for compounds in which R isan ester-containing group.

The compounds of this invention are advantageously administeredtopically to the eye in the form of a solution, ointment, or solidinsert such as is described in U.S. Pat. No. 4,195,085. Formulations maycontain the active compound, preferably, in the form of a soluble acidaddition salt, in amounts ranging from about 0.01% to about 10% by wt.,preferably, from about 0.5% to about 5% by wt. Unit dosages of theactive compound can range from about 0.001 to about 5.0 mg., preferablyfrom about 0.05 to about 2.0 mg. The dosage administered to a patientwill depend upon the patient's needs and the particular compoundsemployed.

Carriers used in the preparations of the present invention arepreferably non-toxic pharmaceutical organic or inorganic compositionssuch as water; mixtures of water and water-miscible solvents, such aslower alcohols; mineral oils; petroleum jellies; ethyl cellulose;polyvinylpyrrolidone and other conventional carriers. In addition, thepharmaceutical preparations may also contain additional components suchas emulsifying, preserving, wetting and sterilizing agents. Theseinclude polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000,1,500, 4,000, 6,000 and 10,000, bacteriocidal components such asquaternary ammonium compounds, phenylmercuric salts known to have coldsterilizing properties and which are non-injurious in use, thimerosal,methyl and propyl paraben, benzyl alcohol, phenyl ethanol, bufferingingredients such as sodium chloride, sodium borate, sodium acetates,gluconate buffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, oleate, polyoxyethylene sorbitanmonopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,thiosorbitol, ethylenediamine tetracetic acid, and the like.Additionally, suitable ophthalmic vehicles can be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems, isotonic boric acid vehicles, isotonic sodium chloridevehicles, isotonic sodium borate vehicles and the like.

The method of treatment of this invention advantageously involves thetopical administration of eye drops containing the active compound.Formulations for eye drops preferably include the active compound as asoluble acid addition salt in a properly buffered, sterile, aqueousisotonic solution.

The compounds of the present invention are ester group-containingbeta-blockers that have a selective, localized, beta-blocking effect inthe eye after topical administration. Such compounds are thought to berapidly metabolized by plasma and/or liver esterases into inactiveby-products, upon entering the systemic circulation. It has beendiscovered that these same compounds are relatively stable in ocularfluids, i.e., lacrimal fluids and aqueous humor. Consequently, suchcompounds are useful for the treatment of glaucoma or for loweringintraocular pressure since they remain stable when topically applied tothe eye but rapidly metabolize when subsequently absorbed into thesystemic circulation.

Some of the compounds break down into the aqueous humor more rapidlythan others. Such compounds may advantageously be employed when only atemporary reduction in intraocular pressure is desired, say fordiagnostic procedures. Longer-acting compounds are generally used foreffecting longer-term reductions in intraocular pressure, such as isdesired when treating chronic glaucoma. Thus, the method of the presentinvention provides a very useful therapeutic alternative for thetreatment of glaucoma or for lowering intraocular pressure.

The in vitro studies hereinafter described indicate that the compoundsused in the method of the present invention will undergo different ratesof enzymatic hydrolysis depending on their location within the body (SeeTable I). For example, compound of Example III is completely hydrolyzedwithin 60 minutes in both dog blood and liver homogenate while only 19%hydrolyzed after one hour in aqueous humor, and only 51.9% hydrolyzedafter two hours. Compound of Example IV is less stable in aqueous humor,hydrolyzing 61.4% after one hour, 100% after two hours.

The present invention is further illustrated by the following exampleswhich are not intended to be limiting.

EXAMPLE I

This example describes the synthesis of a compound of the formula:##STR8##

2,3 Epoxypropyl-2-chlorobenzoate

A mixture containing 14.8 g (0.2 mole) of glycidol, 150 ml of anhydrousether, 16 g (0.4 mole) of pyridine and 35.2 g (0.2 mole) of2-chlorobenzoyl chloride was stirred at room temperature for two hours.The mixture was filtered and the ether was evaporated to leave an oil.This oil was distilled to give a colorless oil. The NMR and IR spectrawere consistent with the assigned structure.

[3-(Isopropylamino)-2-hydroxy]propyl 2-chlorobenzoate hydrochloride

To 1 g of the epoxide from the previous experiment were added 10 g ofisopropylamine. The resultant solution was refluxed for 16 hours andevaporated to dryness. The oily residue was chromatographed on a column(silica gel/EtOH:CH₂ Cl₂ =1.5:3.5) to yield the free amine product. Theamine was converted to its HCl salt by addition of ethereal HCl. Theamine salt was collected by filtration and recrystallized in 2-propanolto give white crystals: m.p. 129° C. The NMR and IR spectra wereconsistent with the assigned structure and the elemental analysis wasconsistent with the empirical formula C₁₃ H₂₆ O₃ NCl₂.

EXAMPLE Ia

This example describes an alternate synthesis of the compound of ExampleI.

3-(Isopropylamino)-1,2-propanediol

A mixture of 37 g (0.5 mole) of glycidol and 35.4 g (0.6 mole) ofisopropylamine was stirred at 25° C. overnight. Excess isopropylaminewas evaporated in vacuo and the mixture was distilled to give 53 g ofproduct: b.p. 80° C./0.1 mm Hg. The NMR and IR spectra were consistentwith the assigned structure and the elemental analysis was consistentwith the empirical formula C₆ H₁₅ O₂ N.

[3-(Isopropylamino)-2-hydroxy]propyl 2-chlorobenzoate hydrochloride

A solution of 10 g (75 mmole) of the diol from the previous experimentand 5.9 g (75 mmole) of pyridine hydrochloride in 20 ml of pyridine wastreated with 13.1 g (75 mmole) of 2-chlorobenzoyl chloride. The mixturewas stirred at room temperature for two hours and 100 ml of water wasadded. The pyridine was evaporated in vacuo at 55°-60° C. and theaqueous solution was washed with 100 ml of ether. The aqueous layer wasthen basified with K₂ CO₃ and extracted with methylene chloride. Themethylene chloride layer was acidified with ether-HCl and evaporated todryness. The residue was crystallized in 2-propanol to give 12.5 g (54%)of product: m.p. 129° C.

EXAMPLE II

This example describes the synthesis of a compound of the formula:##STR9##

The experiment of Example Ia was repeated in all essential details toproduce the above compound, except the reactant 4-fluorobenzoyl chloridewas substituted for 2-chlorobenzoyl chloride. The compound was preparedas the acid addition salt. The compound was identified by NMR and IRspectroscopy, elemental analysis, and had a melting point of 139°-140°C.

EXAMPLE III

This example describes the synthesis of a compound of the formula:##STR10##

The experiment of Example Ia was repeated in all essential details toproduce the above compound, except the reactants t-butylamine andbenzoyl chloride were substituted for isopropylamine and 2-chlorobenzoylchloride, respectively. The compound was prepared as the acid additionsalt. The compound was identified by NMR and IR spectroscopy, elementalanalysis, and had a melting point of 105°-106° C.

EXAMPLE IV

This example describes the synthesis of a compound of the formula:##STR11##

The experiment of Example Ia was repeated in all essential details toproduce the above compound, except the reactants t-butylamine and2-fluorobenzoyl chloride were substituted for isopropylamine and2-chlorobenzoyl chloride, respectively. The compound was prepared as thefree base. The compound was identified by NMR and IR spectroscopy,elemental analysis, and had a melting point of 97.5°-98° C.

EXAMPLES V-VIII

The enzymatic hydrolysis rates of the compounds of Examples I-IV wereexamined in dog blood, liver homogenate, and aqueous humor. All of thecompounds tested were synthesized in accordance with the previousexamples. Acetonitrile was "HPLC" grade. Distilled water was used todissolve the compounds and 0.01N HCl was used to dissolve compoundsrequiring an acidic pH for dissolution.

Fresh aqueous humor was collected from eyes of dogs using a 23 gaugeneedle while fresh dog blood was collected into heparinized Vacutainer®tubes. Fresh liver was homogenized in 0.9% NaCl using a Potter-ElvehjemTeflon pestle and glass homogenizer making a 25% (W/V) honogenate.

A 0.5 ml aliquot of dog aqueous humor, blood, or liver homogenate wasincubated with 12.5 μg (0.5 ml) of beta-blocker in a Dubnoff shakingmetabolic incubator at 37° C. for 60 and 120 minutes. Denatured tissuecontrols were prepared by adding 2.0 ml of acetonitrile into 0.5 ml ofaqueous humor, blood, or liver homogenate to destroy esterase activitiesprior to addition of the beta-blockers. These controls were thenincubated at 37° C. for 120 minutes. After 60 and 120 minutes, theincubations were terminated by addition of 2 ml of acetonitrile andimmediately mixed using a Vortex® mixer to stop esterase activities.

All samples were centrifuged at 4000 RPM for 10 minutes to sedimentdenatured proteins. The resultant supernatants were transferred to WISP®vials and analyzed by high pressure liquid chromatography. Thehydrolysis of beta-blockers in aqueous humor, blood, and liverhomogenate was determined by disappearance of the compounds. The extentof enzymatic hydrolysis in each tissue was determined by comparing theamount of each compound (absolute peak area) recovered at each timepoint to the amount of each compound (absolute peak area) in denaturedtissue control and aqueous control samples.

All of the compounds examined were initially tested for chemicalhydrolysis in 0.1N potassium phosphate buffer, pH 7.40, and all werefound to be stable for at least three hours (data not shown).

Table 1 summarizes the results of these experiments. The extent ofhydrolysis is expressed in terms of the amount of each compoundrecovered after the incubation period relative to the amount of eachcompound recovered in the denatured tissue control. Most of the betablockers were hydrolyzed very rapidly (≧90% in 120 minutes) whenincubated with dog blood and liver homogenate. In contrast, all of thecompounds tested were resistant to enzymatic hydrolysis by esterases indog aqueous humor having hydrolysis rates of 19-61% in 60 minutes and52-100% in 120 minutes.

EXAMPLE IX

This example describes the synthesis of a compound of the formula:##STR12##

2,3 Epoxypropyl 4-[(Methoxycarbonyl)methyl]benzoate

A mixture containing 14.8 g (0.2 mole) of glycidol, 150 ml of anhydrousether, 16 g (0.4 mole of pyridine and 43 g (0.2 mole) of4-[(methoxycarbonyl)methyl]benzoyl chloride is stirred at roomtemperature for two hours. The mixture is filtered and the etherevaporated to leave an oil. This oil is distilled to give a colorlessoil.

[3-(Isopropylamino)-2-hydroxy]propyl 4-[(Methoxycarbonyl)methyl]benzoateHydrochloride

To 1.6 g of the epoxide from the previous experiment is added 10 g ofisopropylamine. The resultant solution is refluxed for 16 hours andevaporated to dryness. The oily residue is chromatographed on a column(silica gel/EtOH:CH₂ Cl₂ =1.5:3.5) to the free amine product. The aminewas converted to its HCl salt by addition of ethereal HCl. The aminesalt was collected by filtration and recrystallized in 2-propanol togive white crystals.

EXAMPLE X

This example describes the synthesis of a compound of the formula:##STR13##

3-[N-[(4-methoxybenzyl)oxycarbonyl]-N-(3,4-dimethoxyphenethyl)]amino-1,2-propanediol

A mixture of 26 g (0.102 mole) of3-(3,4-dimethoxyphenethyl)amino-1,2-propanediol, 29 g (0.345 mole) ofsodium bicarbonate and 24 g (0.116 mole) of p-methoxybenzyloxycarbonylazide in 200 ml of dioxane and 10 ml of water was stirred at roomtemperature for 24 hours. After evaporation of the dioxane in vacuo, theresidue was partitioned between water and CHCl₃. Evaporation of CHCl₃gave an oil which was purified by chromatography (silica gel/10% ethanolin methylene chloride) to give 13 g (30.5%) of product.

[2-Hydroxy-3-[[N-[(4-Methoxybenzyl)oxycarbonyl]-N-(3,4-dimethoxyphenethyl)]amino]propyl4-formyl]benzoate

The diol from the previous experiment was allowed to react with4-formylbenzoyl chloride in a similar manner as described in thepreparation of [2-Hydroxy-3-(isopropylamino)]propyl 2-chlorobenzoatehydrochloride in Example II. The product was purified by chromatography(silica gel/2% ethanol in ether). The yield was 27%.

[2-Hydroxy-3-[(3,4-dimethoxyphenethyl)amino]propyl4-(hydroxymethyl)benzoate]oxalate

The aldehyde obtained from the previous experiment was dissolved inethanol. The resulting solution was cooled to 0° C. and sodiumborohydride in a molar amount equal to the molar amount of the aldehydewas added. The reaction mixture was stirred at 0° C. for ten minutes andexcess hydride was destroyed by addition of water. The crude product wasdissolved in ether-HCl and stirred at room temperature for two hours.The ether was evaporated to dryness and the product was partitionedbetween 5% K₂ CO₃ and methylene chloride. A solution of oxalic acid in2-propanol was added to the methylene chloride layer and the precipitatewas recrystallized in ethanol to give the desired product in 19% yield;m.p. 164°-164.5° C. The NMR and IR spectra were consistent with theassigned structure and the elemental analysis was consistent with theempirical formula C₂₃ H₂₉ NO₁₀.

EXAMPLE XI

This example describes the synthesis of a compound of the followingformula via Method I. ##STR14##

2,3-Epoxypropyl 2-Fluorobenzoate

A mixture containing 37 g (0.5 mole) of glycidol, 500 ml of anhydrousether, 500 ml of pyridine and 80 g (0.5 mole) of o-fluoro-benzoylchloride was stirred at 0° C. for 1 hour and 25° C. for 2 hours. Themixture was filtered and the ethanol filtrate was washed with 100 ml of5% HCl. Evaporation of the ether gave an oil which was distilled to give69.5 g (71%) of product, b.p. 115° C./0.5 mmHg. The NMR and IR spectrawere consistent with the assigned structure.

3-(1,1-Dimethylpropargylamino)-2-hydroxypropyl 2-Fluorobenzoate Oxalate

To 9 g (0.046 mole) of the epoxide from the previous experiment in 50 mlof THF was added 8.5 g (0.092 mole) of 1,1-dimethylpropargylamine. Thereaction mixture was refluxed for 16 hours and evaporated to dryness.The residue was dissolved in 100 ml of iPrOH and 6.5 g (0.07 mole) ofoxalic acid was added. Addition of 50 ml of ether into the iPrOHsolution induced crystallization of the desired product, 3.84 g (23%);m.p. 124°-5°. The NMR and IR spectra were consistent with the assignedstructure and elemental analysis was consistent with the empiricalformula C₁₇ H₂₀ NO₇ F.

EXAMPLE XII

The example describes the synthesis of a compound of the followingformula via Method II. ##STR15##

Ethyl 3,4-Dihydroxybenzoate

A mixture which contained 43 g (0.28 mole) of 3,4-dihydroxybenzoic acid,300 ml of ethanol and 0.5 ml of concentrated H₂ SO₄ was refluxed for 48hours. Water was trapped with 3 Å molecular sieves. The reaction mixturewas evaporated to dryness in vacuo, and partitioned between ether and 5%NaHCO₃ solution. The ether layer was evaporated to give 39 g (69% ) ofsolid; m.p. 128°-130° C. The NMR and IR spectra were consistent with theassigned structure.

3,4-Dibenzyloxybenzoic Acid

To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methylethyl ketone was added 105.5 g (0.76 mole) of K₂ CO₃ and 168.8 g (0.76mole) of benzyl bromide. The mixture was refluxed for 16 hours andfiltered. Evaporation of the filtration gave an oil. This oil was mixedwith 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxedfor 2.5 hours. The methanol was evaporated and the reaction mixture wasacidified with concentrated HCl. The precipitate was filtered to give101 g (92%) of the desired product; m.p. 184°-5° C. The NMR and IRspectra were consistent with the assigned structure.

3-t-Butylamino-2-hydroxypropyl 3,4-dibenzyloxybenzoate

To 20 g (0.06 mole) of the 3,4-dibenzyloxybenzoic acid in 200 ml oftoluene was added 60 g (0.33 mole) of thionyl chloride. The reactionmixture was evaporated to dryness in vacuo to give a solid; m.p.85°-86°. The solid was dissolved in 100 ml of dry THF and added dropwiseinto a solution of 17.7 g (0.06 mole) 3-(t-butylamino)-1,2-propanediolin 50 ml of pyridine and 50 ml of toluene. The reaction mixture wasstirred for 1 hour at 25° C. and partitioned between ether and 5% K₂ CO₃solution. The ether layer was evaporated to dryness to give 30 g ofsolid.

3-tert-Butylamino-2-hydroxypropyl 3,4-Dihydroxybenzoate Hydrochloride

To 25 g of the dibenzyloxybenzoate obtained from the previous experimentwas added 50 ml of ether and acidified with hydrogen chloride. The etherlayer was decanted and the oily residue was dissolved in 200 ml ofmethanol with 2 g of 10% Pd/catalyst. The mixture was agitated for 16hours under 50 psi of hydrogen. The catalyst was filtered and thefiltrate was evaporated to dryness. The product was crystallized iniPrOH to give 14 g (73%) of the product; m.p. 201°-202°. The NMR and IRspectra were consistent with the assigned structure and elementalanalysis was consistent with the empirical formula C₁₄ H₂₂ NO₅ Cl.

EXAMPLES XIII-XV

The experiment of Example XII was repeated in all essential detail toproduce Examples XIII-XV described in Table 2 except that differentbenzyloxybenzoic acids were used to react with the3-(t-butyl-amino)-1,2-propanediols. Each of the compounds was identifiedby NMR, IR and elemental analysis.

EXAMPLES XVI and XVII

The procedure for the preparation of 3-t-butylamino-2-hydroxypropyl3,4-dibenzyloxybenzoate in Example XII was repeated in all essentialdetail to produce Example XVII described in Table 2 except that3,4-dipivaloyloxy benzoic acid was used to react with the3-(tert-butylamino)-1,2-propanediol. The crude product of Example XVIIwas chromatographed on silica gel with 10% EtOH in EtoAc to give ExampleXVI.

The NMR and IR spectra were consistent with the assigned structures.Comparative data relating to Examples XI to XVII are given in Table 2.

EXAMPLE XVIII

The intraocular pressure lowering effect of the compounds described inExamples I-IV and IX-XVII are demonstrated in rabbits with normotensiveeyes.

Sterile, isotonic saline solutions of each of the compounds prepared inprocedures of Examples I-IV, IX-XVII are prepared by dissolving 10, 30and 100 mg samples of each of the active compounds in 1 ml of saline togive 1%, 3% and 10% solutions with pH about 6.0-7.0. Free amines requireone equivalent of HCl to effect dissolution.

The intraocular pressure lowering effect of each compound is determinedby treating the eyes of healthy rabbits with the above solutions. Threerabbits are used to evaluate the effect of each drug concentration. Astandard dose of 50 μl of each drug solution is applied to one eye ofeach of the three rabbits. Intraocular pressure of both eyes is measuredwith a pressure tonograph or a MacKay-Marg Tonometer before drugadministration and at 15, 30, 45, 60, 120, 180, 240, 300, 360, 420 and480 minutes after dosing. Control rabbits are treated similarly withsterile isotonic saline solution. Intraocular pressure lowering in thetreated eyes is compared with the untreated eyes, with saline treatedeyes and with predrug pressures. All of the test compounds showintraocular pressure-lowering activity.

EXAMPLE XIX

The experiment of Example XVIII is repeated in all essential details,except that rabbits which have corticosteroid-induced ocularhypertension, as described by Bonomi, L., et al., Glaucoma, Eds. R.Pittscrick, A. D. S. Caldwell, Academic Press, New York, pp. 98-107(1980), are substituted for the normotensive rabbits. Each of the testcompounds exhibits intraocular pressure-lowering activity in this model.

                  TABLE 1                                                         ______________________________________                                        ENZYMATIC HYDROLYSIS OF                                                       BETA BLOCKERS BY DOG BLOOD                                                    LIVER HOMOGENATE, AND AQUEOUS HUMOR                                                        % HYDROLYZED                                                                                        AQUE-                                                                         OUS                                        COMPOUND       BLOOD     LIVER     HUMOR                                      EXAM-  OF          60     120  60   120  60   120                             PLE    EXAMPLE     min    min  min  min  min  min                             ______________________________________                                        V      III         100    100  100  100  18.9 51.9                            VI     II          100    100  100  100  21.9 61.8                            VII    I, Ia       77.4   90.8 90.1 96.1 39.2 71.6                            VIII   IV          100    100  100  100  61.4 100                             ______________________________________                                         .sup.1 Data at each time point are expressed relative to denatured tissue     control.                                                                 

                                      TABLE 2                                     __________________________________________________________________________     ##STR16##                                                                                                         Add. Crystn.                             Example                                                                            Ar          R         Method                                                                             Yield %                                                                            Salt Solvent                             __________________________________________________________________________    XI                                                                                  ##STR17##  C(CH.sub.3).sub.2 CCH                                                                    I   22.7 (COOH).sub.2                                                                       iPrOHEt.sub.2 O                     XII                                                                                 ##STR18##  C(CH.sub.3).sub.3                                                                       II   73   HCl  iPrOH                               XIII                                                                                ##STR19##  CH(CH.sub.3).sub.2                                                                      II   45   (COOH).sub.2                                                                       Acetone EtOAC                       XIV                                                                                 ##STR20##  C(CH.sub.3).sub.3                                                                       II   58   HCl  Acetone EtOAc                       XV                                                                                  ##STR21##  C(CH.sub.3).sub.3                                                                       II   86   HCl  Acetone                             XVI                                                                                 ##STR22##  C(CH.sub.3).sub.3                                                                       II   3    --   --                                  XVII                                                                                ##STR23##  C(CH.sub.3).sub.3                                                                       II   21   --   Oil                                 __________________________________________________________________________

We claim:
 1. A compound of the formula ##STR24## wherein R is lowerhydroxyalkyl or lower alkynyl and Ar is substituted or unsubstitutedaromatic; with the proviso that when Ar is phenyl substituted with 2 or3 hydroxy groups, or phenyl substituted with acyloxy wherein the acylportion is alkanoyl of from 2 to about 5 carbon atoms or benzoyl(optionally substituted by halogen, alkoxy, alkyl or hydroxy), R mayoptionally additionally be isopropyl, t-butyl or dimethoxyphenethyl; ora pharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein R is lower hydroxyalkyl of from 2 to about 7 carbon atoms orlower alkynyl of from 3 to about 10 carbon atoms, and Ar isunsubstituted phenyl or phenyl substituted with lower alkyl of from 1 toabout 5 carbon atoms, fluoro, chloro, nitro, hydroxy, amino, acyloxy,wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atomsor unsubstituted benzoyl or benzoyl substituted with halogen, loweralkoxy, lower alkyl, hydroxy or a group of the formula ##STR25## whereinR₁ is lower alkyl of from 1 to about 5 carbon atoms and n is an integerfrom 0 to about
 5. 3. The compound of claim 1, wherein R is lowerhydroxyalkyl of from 2 to about 5 carbon atoms or lower alkynyl of from3 to about 5 carbon atoms, and Ar is unsubstituted phenyl or phenylsubstituted with methyl, fluoro, chloro, nitro hydroxy, amino, ofacyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5carbon atoms, or unsubstituted benzoyl or benzoyl substituted withhalogen, lower alkyl or hydroxy.
 4. The compound of claim 1, wherein Ris hydroxy-t-butyl or dimethylpropargyl and Ar is phenyl,2-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, hydroxyphenyl, dihydroxyphenyl, (pivaloyloxy)phenyl or (dipivaloyloxy)phenyl.
 5. The compound ofclaim 1 of the formula ##STR26## wherein R is isopropyl, t-butyl,dimethylpropargyl, hydroxy-t-butyl or dimethoxyphenethyl, n is 2 or 3.6. The compound of claim 1 of the formula ##STR27## wherein R isisopropyl, t-butyl, dimethylpropargyl, hydroxy-t-butyl ordimethoxyphenethyl and acyl is alkanoyl of from 2 to about 5 carbonatoms, or benzoyl, optionally substituted by halogen, alkoxy, alkyl orhydroxy.
 7. The compound of claim 1 of the formula ##STR28##
 8. Thecompound of claim 1 of the formula ##STR29##
 9. The compound of claim 1of the formula ##STR30##
 10. The compound of claim 1 of the formula##STR31##
 11. The compound of claim 1 of the formula ##STR32##
 12. Thecompound of claim 1 of the formula ##STR33##
 13. The compound of claim 1of the formula ##STR34##